Biosimilars are unlikely to be manufactured by conventional bioprocessing strategies—those used by biopharma companies and contract manufacturing organizations (CMOs) over the past 20-plus years. Rather, a number of alternative paths to traditional CMO, and in-house bioprocessing are already emerging.

There are many regional manufacturers, not only in major markets, but in emerging areas where an increasing number of companies are getting involved with biosimilars, both developers and CMOs. While in the past, many generally had no experience in cGMP production, this, too, is changing. More partnerships among regional biopharma companies and biosimilars developers and CMOs are also being formed.

So it is unlikely that the biosimilars industry today, will resemble the segment in five or 10 years. CMOs are likely to play an important role, yet it may not necessarily be the leading CMOs today that create success or get most of the biosimilars business. CMOs with excellent bioprocessing expertise and process development competence may not necessarily be attracted by the lower margins associated with biosimilars, nor will they be as cost competitive compared with more nimble CMOs that have the needed GMP expertise.

Biosimilars current events
Much has happened during the past year in biosimilars.1 We now have the first two biosimilar products in the U.S.—Zarxio from Sandoz/Novartis, and Inflectra, a monoclonal antibody (mAb) from Janssen Biotech/Johnson & Johnson. These were approved by FDA with no apparent significant problems. Inflectra is the first approval of a biosimilar mAb, a class of products only a few years ago presumed by many to likely require substantial FDA biosimilars regulation before gaining sufficient confidence to grant approvals. Plus, at least several more biosimilar applications will be considered by FDA this year. Soon enough, biosimilars will begin to make a real impact, begin to be noticed and become part of mainstream medical care in the U.S., the major single market for biopharmaceutical products. In the meantime, the more established biosimilar markets in European and other major markets continue to mature, with more biosimilars entering the market and these continuing to incrementally capture increasing market share and displace their reference products. Internationally, the number and use of biogenerics continue to increase, with these products often cited as ‘biosimilars,’ generally manufactured and marketed in lesser- and non-regulated countries, and generally not meeting major market, e.g., U.S. or EU, analytical and clinical testing and manufacturing (GMP) standards for biosimilars or biopharmaceuticals. However, as discussed below, many aspects of the current and future biosimilars market remain uncertain, including many aspects related to product development and manufacturing, including the role of CMOs.

So far, biosimilars development and approvals has proven to not be as hard as many had originally projected it would be. This includes no recent major market filings having been rejected, no manufacturing halted due to regulatory agency inspection failures, no abandonment of the field by developers or investors, etc. In fact, the field, including the number of companies involved, products in development and their stages of development continue to slowly but steadily increase. This includes the number of biosimilars products in the development pipeline and related numbers of involved manufacturers and marketers.

The Biosimilars/Biobetters Pipeline Database online from BioPlan Associates2 now reports over 730 biosimilar products and over 280 companies worldwide substantively involved in biosimilars development, manufacturing and/or marketing. And biosimilars are slowly advancing in development, as shown in Figure 1.

Although the largest portion of products are in preclinical phases, the number of biosimilars in Phase I and II/III trials continues to increase. There are currently at least 35 candidate biosimilars in Phase I trials and 62 in Phase II/III trials with there often being little distinction between Phase II- and III-type biosimilars clinical trials. With little or no related major clinical trial or manufacturing failures reported with biosimilars and few expected, it can be presumed that virtually all of these products now in trials will enter the market eventually.

In coming years, patent expirations on relevant reference products will increase, making more biosimilars approvable.1 As these patents expire, many more products now in preclinical stages will advance into clinical trials and subsequently enter the market. Anecdotal evidence indicates that a good portion of developers with products currently in preclinical phases are simply waiting to advance their candidate products into clinical trials as relevant patent expirations approach and/or for FDA to issue more regulations and/or give more actually-useful guidance concerning U.S. biosimilar approvals. A good portion of future major biosimilar players may also be waiting for more U.S. and EU regulations and guidance concerning fully interchangeable biosimilars, with these expected to be marketed much like nearly all A-B interchangeable generic drugs, meaning they will simply be manufactured and available for purchase without the costly marketing and promotion associated with an innovator/reference product. In the meantime, developers and manufacturers in developing countries are continuing to develop and launch into the market an increasing number of biogenerics; an increasing number of these manufacturers will seek to advance to full cGMP manufacturing to make their products licensable and marketable in the U.S., EU and other highly-regulated major markets.

CMOs well-suited for biosimilars
CMOs, anecdotally have reported seeing as much as a 15% increase in the number of projects and revenue from taking-on biosimilars development and manufacturing for clients.1 Beyond this, currently little is actually documented about current and near-term future biosimilar development and manufacturing, including CMO involvement. But it is logical to predict that CMOs are increasingly and significantly involved in biosimilar development and manufacture. In many respects, biosimilars are perfectly suited for CMOs with expertise in cost-efficient manufacturing. Reasons for this include:

Biosimilars, compared to innovative biopharmaceuticals, for most developers are not among their companies highest priorities. They do not generally involve high projected revenue. Rather, biosimilars will continue to impact smaller markets, with biosimilars competing with the reference product, and with each other. This tends to be a good reason to outsource biosimilar development and manufacture.

CMOs have a history of success in developing and manufacturing products, including about 30% of currently marketed major market biopharmaceutical products being manufactured at some scale by a CMO. There is every reason to presume this frequent use of CMOs will carry over to biosimilars.

CMOs generally have much more diverse expertise and equipment than most developer companies, and tend to work efficiently—they simply have to, to remain competitive. CMOs work on many more projects/products using more diverse technologies, and they are more set up for and experienced with flexible and rapid process and product development.

Many CMOs have been or are currently working on multiple biosimilars for clients. This includes sometimes working on biosimilar versions of the same reference product for multiple clients. Thus, many CMOs already have more experience with biosimilars than developer companies, including analytical studies and process development.

CMO use has been proven cost-effective, and use of CMOs provides increased flexibility for developer companies. With market sizes, the number of competitors, and other aspects related to needed biosimilar manufacturing capacity remaining unknown, the flexibility afforded by use of CMOs, including their ability to rapidly ramp-up manufacturing as needed, makes their use more attractive, if not essential.

Associated with their flexibility and high levels of expertise, CMOs, even if not used by developers for product and process development, will increasingly be used as second-source or back-up manufacturing facilities by developer companies that pursue primary product manufacturing in-house.

Single-use systems and other bioprocessing advances are making product development and manufacturing efforts simpler, cheaper and more rapid, including quicker product manufacturing turnover; and advances are continuing to reduce the needed size of bioprocessing hardware, suites and facility footprints. CMOs are particularly well positioned to take advantage of the cost savings, flexibility and other advantages these trends provide.

Resolving biosimilar manufacturing-related uncertainties
While there is much anecdotal reporting about developer company and CMO involvement in biosimilars, to date, there have been no actual studies and no information available concerning many of the bioprocessing-related aspects of current and future biosimilars development and manufacturing. Current unknowns include:

Types of CMO involvement in biosimilar development and commercial manufacturing expected in the future, e.g., in 5 years.

Why are developers hiring CMOs? Should companies plan for preclinical and early trial support, or for commercial manufacturing?

Future manufacturing strategies for commercial biosimilars production by CMOs vs. developers. How should CMOs, and other service providers prepare for biosimilars?

General approaches to product manufacturing, such as using single-use or multi-product suites or facilities; will manufacturing be done in new facilities? Will current monoclonal antibody (mAb) manufacturers produce biosimilar mAbs in existing ≥10,000 L bioreactors, perhaps only partially filling for manufacturing runs?

Will biosimilar manufacturing be more effective in single-use, stainless steel or a hybrid mix of hardware? Will adopting continuous manufacturing options, such as perfusion be a viable option?

Where will developers have their biosimilars manufactured? Major markets; CMOs current or new facilities? Regional manufacturing where costs are presumed to be lower? Will a portion of major market biosimilars be manufactured by CMOs in countries such as India or China?

Will biosimilar be done in modern state-of-the-art operations, or will they attempt to emulate now-legacy reference product manufacturing technologies? So far, current major market developers appear to be manufacturing using modern state-of-the-art technologies. But, given the focus on efficient production, will different expression systems be used? E.g., HEK-293, or switching to E. coli rather than the reference product’s use of CHO.

To resolve these unknowns regarding biosimilar manufacturing and CMO involvement, BioPlan Associates is expanding its public biosimilar development and manufacturing databases. In addition to its Biosimilars/Biobetter Pipeline Database development pipeline tracking database (www.biosimilarspipeline.com), BioPlan has expanded its free Top 1000 Biopharmaceutical Facilities web site (www.top1000bio.com) to include Top 100 Biosimilar Facilities analysis. As with our BioPlan industry projects, including 30-year trends data for in bioprocessing titers and yields,3,4 biosimilars projects aggregate current biosimilars developments to compile all public data.
Because biosimilars manufacturing is plotting uncharted territory in biomanufacturing strategy, we will continue to identify and define the alternative paths to traditional in-house and contract bioprocessing that continues to emerge—especially as they relate to efficient GMP production. The global nature of biomanufacturing also opens a space for manufacturers in developing regions.

While the biosimilars industry is not likely to resemble today’s industry, it’s also safe to project that the efficiencies emerging from the most productive and competitive CMOs are likely to play an important role in the future of bioprocessing at all levels.

Ronald A. Rader is senior director, technical research at BioPlan Associates. Mr. Rader has over 25 years experience as a biotechnology, and pharmaceutical information specialist and publisher, including editor/publisher of Antiviral Agents Bulletin, editor-in-chief of the journal Biopharmaceuticals, and many data resources including Biopharmaceutical Products in the U.S. Market, now in its 12th Ed, and the first biosimilars database.

Eric S. Langer is president and managing partner at BioPlan Associates, a biotechnology and life sciences marketing research and publishing firm established in Rockville, MD in 1989. He is editor of numerous studies, including “Biopharmaceutical Technology in China,” “Advances in Large-scale Biopharmaceutical Manufacturing,” and many other industry reports. elanger@bioplanassociates.com; 301-921-5979; www.bioplanassociates.com